Multiple immunotherapies have demonstrated long-term clinical benefit in patients with melanoma. Clinical trials are currently underway to build upon this activity in melanoma, and to see if similar benefits can be achieved in other cancers. Despite the advances made over the last few years, there is currently limited understanding of the mechanisms of resistance to immunotherapy. An improved understanding of resistance may identify patients that are most likely to benefit from current immunotherapies. Further, identification of resistance mechanisms that are targetable may lead to combinations that are more effective. Previously we demonstrated that targeting BRAFV600 mutations, which are the most common somatic alterations in melanoma, increases the efficacy of immune-mediated killing of tumors through multiple mechanisms, leading to ongoing clinical trials. Recently, we have found evidence that loss of the tumor suppressor PTEN, which occurs in 20-30% of melanomas with BRAFV600 mutations, may also contribute to resistance to immunotherapy. Our preliminary experiments show that loss of PTEN in BRAF-mutant melanoma cells inhibits T-cell mediated killing of melanomas in vitro , decreases intratumoral accumulation of tumor-infiltrating T cells (TIL) in vivo, and correlates with reduced success of TIL expansion from patients. Our data also demonstrates that loss of PTEN correlates with inferior clinical outcomes among BRAF-mutant melanoma patients, reinforcing the clinical significance of this subpopulation. Loss of PTEN results in marked activation of the PI3K-AKT pathway, a pathway for which many targeted agents are available and currently undergoing clinical testing. Thus, our central hypothesis is that the PI3K-AKT pathway in tumor cells is the critical mechanism of resistance to immunotherapy in BRAF-mutant melanomas, and that inhibition of this pathway will increase the efficacy of T-cell mediated immunotherapy. In order to test this hypothesis, we will utilize multiple unique clinical and preclinical resources that we have established to develop more effective therapeutic approaches for melanoma patients. First, we will utilize our preclinical models and diagnostic platforms to interrogate the mechanisms that underlie resistance to T-cell mediated killing and trafficking of T cells to melanoma with loss of PTEN. Second, we will analyze specimens from several cohorts of melanoma patients to determine the immunological features and immunotherapy treatment outcomes associated with PTEN loss. Finally, we will determine the effects of PI3K-AKT pathway inhibitors, alone and in combination with FDA-approved BRAF inhibitors, on T-cell viability, function, and anti-tumor activity in vitro and in vio. Together these studies will improve our understanding of the role and therapeutic potential of the PI3K-AKT pathway in resistance to immunotherapy in melanoma. Further, as the PI3K-AKT pathway is implicated in multiple tumor types in which immunotherapies are being tested, the findings may have broad applications for cancer patients.